NO140101B - PROCEDURES FOR THE PREPARATION OF SUBSTITUTED AMINOBENZO ACID DERIVATIVES - Google Patents
PROCEDURES FOR THE PREPARATION OF SUBSTITUTED AMINOBENZO ACID DERIVATIVES Download PDFInfo
- Publication number
- NO140101B NO140101B NO743211A NO743211A NO140101B NO 140101 B NO140101 B NO 140101B NO 743211 A NO743211 A NO 743211A NO 743211 A NO743211 A NO 743211A NO 140101 B NO140101 B NO 140101B
- Authority
- NO
- Norway
- Prior art keywords
- benzoic acid
- sulfamyl
- phenoxy
- acid
- butylamino
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 5
- 239000002253 acid Substances 0.000 title description 20
- 239000002841 Lewis acid Substances 0.000 claims description 13
- 150000007517 lewis acids Chemical class 0.000 claims description 13
- 229910052796 boron Inorganic materials 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- ZFQWZHGDRRHUBY-UHFFFAOYSA-N 3-amino-5-sulfamoylbenzoic acid Chemical class NC1=CC(C(O)=O)=CC(S(N)(=O)=O)=C1 ZFQWZHGDRRHUBY-UHFFFAOYSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 150000005417 aminobenzoic acid derivatives Chemical class 0.000 abstract 1
- -1 amino compound Chemical class 0.000 description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 18
- 239000005711 Benzoic acid Substances 0.000 description 17
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000012279 sodium borohydride Substances 0.000 description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000003638 chemical reducing agent Substances 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 238000009835 boiling Methods 0.000 description 5
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 5
- MAEIEVLCKWDQJH-UHFFFAOYSA-N bumetanide Chemical compound CCCCNC1=CC(C(O)=O)=CC(S(N)(=O)=O)=C1OC1=CC=CC=C1 MAEIEVLCKWDQJH-UHFFFAOYSA-N 0.000 description 5
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- KXIDZTLANKUQPQ-UHFFFAOYSA-N methyl 3-(butylamino)-4-phenoxy-5-sulfamoylbenzoate Chemical compound CCCCNC1=CC(C(=O)OC)=CC(S(N)(=O)=O)=C1OC1=CC=CC=C1 KXIDZTLANKUQPQ-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229910015900 BF3 Inorganic materials 0.000 description 2
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 150000001733 carboxylic acid esters Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- ZBABAZCKMZJFMU-UHFFFAOYSA-N (4-methoxyphenyl)methyl 3-(butylamino)-5-(decoxymethylsulfamoyl)-4-phenoxybenzoate Chemical compound CCCCCCCCCCOCNS(=O)(=O)C1=CC(C(=O)OCC=2C=CC(OC)=CC=2)=CC(NCCCC)=C1OC1=CC=CC=C1 ZBABAZCKMZJFMU-UHFFFAOYSA-N 0.000 description 1
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- URUDDWPCRNOQER-UHFFFAOYSA-N 3-(2-methoxyethylamino)-4-phenylsulfanyl-5-sulfamoylbenzoic acid Chemical compound COCCNC1=CC(C(O)=O)=CC(S(N)(=O)=O)=C1SC1=CC=CC=C1 URUDDWPCRNOQER-UHFFFAOYSA-N 0.000 description 1
- PUIUOPTWELLSSI-UHFFFAOYSA-N 3-(2-phenylethylamino)-4-phenylsulfanyl-5-sulfamoylbenzoic acid Chemical compound C=1C=CC=CC=1SC=1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1NCCC1=CC=CC=C1 PUIUOPTWELLSSI-UHFFFAOYSA-N 0.000 description 1
- WBUCYKAFHSJJNJ-UHFFFAOYSA-N 3-(4-hydroxybutylamino)-4-phenoxy-5-sulfamoylbenzoic acid Chemical compound NS(=O)(=O)C1=CC(C(O)=O)=CC(NCCCCO)=C1OC1=CC=CC=C1 WBUCYKAFHSJJNJ-UHFFFAOYSA-N 0.000 description 1
- BOXFZVYRTBSYEK-UHFFFAOYSA-N 3-(4-hydroxybutylamino)-4-phenylsulfanyl-5-sulfamoylbenzoic acid Chemical compound NS(=O)(=O)C1=CC(C(O)=O)=CC(NCCCCO)=C1SC1=CC=CC=C1 BOXFZVYRTBSYEK-UHFFFAOYSA-N 0.000 description 1
- UCNWQTMKAPAUHU-UHFFFAOYSA-N 3-(benzylamino)-4-phenoxy-5-sulfamoylbenzoic acid Chemical compound C=1C=CC=CC=1OC=1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1NCC1=CC=CC=C1 UCNWQTMKAPAUHU-UHFFFAOYSA-N 0.000 description 1
- DXLANCVSXGODDB-UHFFFAOYSA-N 3-(benzylamino)-4-phenylsulfanyl-5-sulfamoylbenzoic acid Chemical compound C=1C=CC=CC=1SC=1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1NCC1=CC=CC=C1 DXLANCVSXGODDB-UHFFFAOYSA-N 0.000 description 1
- APZLLAQFAMQGMV-UHFFFAOYSA-N 3-(butanoylamino)-4-phenoxy-5-sulfamoylbenzoic acid Chemical compound CCCC(=O)NC1=CC(C(O)=O)=CC(S(N)(=O)=O)=C1OC1=CC=CC=C1 APZLLAQFAMQGMV-UHFFFAOYSA-N 0.000 description 1
- NWYUVKPGSQYOQU-UHFFFAOYSA-N 3-(cyclobutylmethylamino)-4-phenylsulfanyl-5-sulfamoylbenzoic acid Chemical compound C=1C=CC=CC=1SC=1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1NCC1CCC1 NWYUVKPGSQYOQU-UHFFFAOYSA-N 0.000 description 1
- MKOFSDUQCWFPIG-UHFFFAOYSA-N 3-(cyclopropylmethylamino)-4-phenoxy-5-sulfamoylbenzoic acid Chemical compound C=1C=CC=CC=1OC=1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1NCC1CC1 MKOFSDUQCWFPIG-UHFFFAOYSA-N 0.000 description 1
- ISTCGIYVZKGRGT-UHFFFAOYSA-N 3-(cyclopropylmethylamino)-4-phenylsulfanyl-5-sulfamoylbenzoic acid Chemical compound C=1C=CC=CC=1SC=1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1NCC1CC1 ISTCGIYVZKGRGT-UHFFFAOYSA-N 0.000 description 1
- KQDOWULTFRAYRS-UHFFFAOYSA-N 3-(furan-2-ylmethylamino)-4-phenoxy-5-sulfamoylbenzoic acid Chemical compound C=1C=CC=CC=1OC=1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1NCC1=CC=CO1 KQDOWULTFRAYRS-UHFFFAOYSA-N 0.000 description 1
- GVQZPZSQRCXSJI-UHFFFAOYSA-N 3-amino-4-phenoxy-5-sulfamoylbenzoic acid Chemical compound NC1=CC(C(O)=O)=CC(S(N)(=O)=O)=C1OC1=CC=CC=C1 GVQZPZSQRCXSJI-UHFFFAOYSA-N 0.000 description 1
- XFDUHJPVQKIXHO-UHFFFAOYSA-N 3-aminobenzoic acid Chemical class NC1=CC=CC(C(O)=O)=C1 XFDUHJPVQKIXHO-UHFFFAOYSA-N 0.000 description 1
- KKBUZGMMGNIJRN-UHFFFAOYSA-N 4-(2,4-dimethylphenoxy)-3-(2-phenylethylamino)-2-sulfamoylbenzoic acid Chemical compound CC1=CC(C)=CC=C1OC1=CC=C(C(O)=O)C(S(N)(=O)=O)=C1NCCC1=CC=CC=C1 KKBUZGMMGNIJRN-UHFFFAOYSA-N 0.000 description 1
- VZPPIIKJHWFLQD-UHFFFAOYSA-N 4-(4-aminophenoxy)-3-(2-phenylethylamino)-2-sulfamoylbenzoic acid Chemical compound C1=CC(N)=CC=C1OC1=CC=C(C(O)=O)C(S(N)(=O)=O)=C1NCCC1=CC=CC=C1 VZPPIIKJHWFLQD-UHFFFAOYSA-N 0.000 description 1
- NLKIIQIFPBHBGW-UHFFFAOYSA-N 4-(4-chlorophenoxy)-3-(2-phenylethylamino)-2-sulfamoylbenzoic acid Chemical compound C=1C=C(Cl)C=CC=1OC1=CC=C(C(O)=O)C(S(=O)(=O)N)=C1NCCC1=CC=CC=C1 NLKIIQIFPBHBGW-UHFFFAOYSA-N 0.000 description 1
- AZACEUYDFUKMQN-UHFFFAOYSA-N 4-(4-methoxyphenoxy)-3-(2-phenylethylamino)-2-sulfamoylbenzoic acid Chemical compound C1=CC(OC)=CC=C1OC1=CC=C(C(O)=O)C(S(N)(=O)=O)=C1NCCC1=CC=CC=C1 AZACEUYDFUKMQN-UHFFFAOYSA-N 0.000 description 1
- BSUYBMBAHUWPIO-UHFFFAOYSA-N 4-(4-methylphenoxy)-3-(2-phenylethylamino)-2-sulfamoylbenzoic acid Chemical compound C1=CC(C)=CC=C1OC1=CC=C(C(O)=O)C(S(N)(=O)=O)=C1NCCC1=CC=CC=C1 BSUYBMBAHUWPIO-UHFFFAOYSA-N 0.000 description 1
- WPBIAQLHXLVMJF-UHFFFAOYSA-N 4-[4-(ethylamino)phenoxy]-3-(2-phenylethylamino)-2-sulfamoylbenzoic acid Chemical compound C1=CC(NCC)=CC=C1OC1=CC=C(C(O)=O)C(S(N)(=O)=O)=C1NCCC1=CC=CC=C1 WPBIAQLHXLVMJF-UHFFFAOYSA-N 0.000 description 1
- FBEPHCVLIQENOX-UHFFFAOYSA-N 4-benzyl-3-(2-methoxyethylamino)-5-sulfamoylbenzoic acid Chemical compound COCCNC1=CC(C(O)=O)=CC(S(N)(=O)=O)=C1CC1=CC=CC=C1 FBEPHCVLIQENOX-UHFFFAOYSA-N 0.000 description 1
- SGEHZQCWLGQERJ-UHFFFAOYSA-N 4-benzyl-3-(2-phenylethylamino)-5-sulfamoylbenzoic acid Chemical compound C=1C=CC=CC=1CC=1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1NCCC1=CC=CC=C1 SGEHZQCWLGQERJ-UHFFFAOYSA-N 0.000 description 1
- NHSVUJIWJWGNIZ-UHFFFAOYSA-N 4-benzyl-3-(4-hydroxybutylamino)-5-sulfamoylbenzoic acid Chemical compound NS(=O)(=O)C1=CC(C(O)=O)=CC(NCCCCO)=C1CC1=CC=CC=C1 NHSVUJIWJWGNIZ-UHFFFAOYSA-N 0.000 description 1
- QETFFKSYPSDMFB-UHFFFAOYSA-N 4-benzyl-3-(benzylamino)-5-sulfamoylbenzoic acid Chemical compound C=1C=CC=CC=1CC=1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1NCC1=CC=CC=C1 QETFFKSYPSDMFB-UHFFFAOYSA-N 0.000 description 1
- KXFIWUUBVFRPIZ-UHFFFAOYSA-N 4-benzyl-3-(cyclobutylmethylamino)-5-sulfamoylbenzoic acid Chemical compound C=1C=CC=CC=1CC=1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1NCC1CCC1 KXFIWUUBVFRPIZ-UHFFFAOYSA-N 0.000 description 1
- FMFHIXTVXROQMK-UHFFFAOYSA-N 4-benzyl-3-(furan-2-ylmethylamino)-5-sulfamoylbenzoic acid Chemical compound C=1C=CC=CC=1CC=1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1NCC1=CC=CO1 FMFHIXTVXROQMK-UHFFFAOYSA-N 0.000 description 1
- RGXMLGOOOUDRJY-UHFFFAOYSA-N 4-phenoxy-3-(2-phenylethylamino)-5-sulfamoylbenzoic acid Chemical compound C=1C=CC=CC=1OC=1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1NCCC1=CC=CC=C1 RGXMLGOOOUDRJY-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000004849 alkoxymethyl group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 238000010640 amide synthesis reaction Methods 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical class B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 239000012084 conversion product Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical class [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- ABZUSEQGNCSQDS-UHFFFAOYSA-N methyl 3-(2-chloroethylamino)-4-phenylsulfanyl-5-sulfamoylbenzoate Chemical compound NS(=O)(=O)C1=CC(C(=O)OC)=CC(NCCCl)=C1SC1=CC=CC=C1 ABZUSEQGNCSQDS-UHFFFAOYSA-N 0.000 description 1
- YUMJAPMUMCJHBI-UHFFFAOYSA-N methyl 3-(benzylsulfamoyl)-5-(butylamino)-4-phenoxybenzoate Chemical compound CCCCNC1=CC(C(=O)OC)=CC(S(=O)(=O)NCC=2C=CC=CC=2)=C1OC1=CC=CC=C1 YUMJAPMUMCJHBI-UHFFFAOYSA-N 0.000 description 1
- VGKUIQWRNJBNJC-UHFFFAOYSA-N methyl 3-amino-4-phenoxy-5-sulfamoylbenzoate Chemical compound NS(=O)(=O)C1=CC(C(=O)OC)=CC(N)=C1OC1=CC=CC=C1 VGKUIQWRNJBNJC-UHFFFAOYSA-N 0.000 description 1
- CIUZLUCAGGEETJ-UHFFFAOYSA-N methyl 4-benzyl-3-(2-chloroethylamino)-5-sulfamoylbenzoate Chemical compound NS(=O)(=O)C1=CC(C(=O)OC)=CC(NCCCl)=C1CC1=CC=CC=C1 CIUZLUCAGGEETJ-UHFFFAOYSA-N 0.000 description 1
- JDYIEBRCGWZVSA-UHFFFAOYSA-N methyl 4-benzyl-3-(3-chloropropylamino)-5-sulfamoylbenzoate Chemical compound NS(=O)(=O)C1=CC(C(=O)OC)=CC(NCCCCl)=C1CC1=CC=CC=C1 JDYIEBRCGWZVSA-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005207 tetraalkylammonium group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Catalysts (AREA)
Abstract
Fremgangsmåte til fremstilling av substituerte aminobenzosyrederivater.Process for the preparation of substituted aminobenzoic acid derivatives.
Description
Oppfinnelsen vedrører en fremgangsmåte til fremstilling av 3-amino-5-sulfamylbenzosyrederivater med formel I The invention relates to a process for the production of 3-amino-5-sulfamylbenzoic acid derivatives with formula I
hvori in which
R betyr hydrogen eller lavere alkyl, R means hydrogen or lower alkyl,
R^ betyr lavere alkyl som eventuelt kan være substituert med en lavere alkoksygruppe, hydroksygruppe eller et halogenatom, eller R^ means lower alkyl which may optionally be substituted with a lower alkoxy group, hydroxy group or a halogen atom, or
R^ betyr en cykloalkylring med 3-6 karbonatomer, en fenyl-eller benzylgruppe, R^ means a cycloalkyl ring with 3-6 carbon atoms, a phenyl or benzyl group,
idet fremgangsmåten er karakterisert ved at 3-acylamino-5-sulfamyl-benzosyrederivater med den generelle formel II in that the method is characterized in that 3-acylamino-5-sulfamyl-benzoic acid derivatives with the general formula II
hvori in which
R- 5 og R^ har ovennevnte betydning, reduseres med borhydrogener eller med komplekse borhydrider i nærvær av Lewis-syrer og eventuelt underkastes 3-amino-5-sulfamyl-benzosyreestrene med formel I, hvori R^ ikke betyr hydrogen, hydrolyse eller hydrogenolyse. R- 5 and R^ have the above meaning, are reduced with boron hydrogens or with complex borohydrides in the presence of Lewis acids and optionally subjected to the 3-amino-5-sulfamyl-benzoic acid esters of formula I, in which R^ does not mean hydrogen, hydrolysis or hydrogenolysis.
Fremgangsmåteproduktene har gode diuretiske egen-skaper . The process products have good diuretic properties.
Noen 3-n-alkylamino-4-fenoksy-5-sulfamylbenzosyre-derivater med formel I har vært kjent i lengre tid. Den hittil kjente fremstilling av de kjente forbindelser er i mange tilfeller ikke tilfredsstillende. Den foregår eksempelvis ved oppvarmning av aminoforbindelsen med formel III (R<1> til R^=H) i nærvær av konsentrert svovelsyre og butanol under tilbakeløp. Etter flere dager har det dannet seg butylesteren av det ønskede produkt som deretter må hydrolyseres. De lange reaksjonstider og faren for dialkylering gjorde det nødvendig å søke etter metoder til å fremstille forbindelser med den generelle formel I under skånende betingelser i bedre romtids-utbytter. Some 3-n-alkylamino-4-phenoxy-5-sulfamylbenzoic acid derivatives of formula I have been known for a long time. The hitherto known preparation of the known compounds is not satisfactory in many cases. It takes place, for example, by heating the amino compound of formula III (R<1> to R^=H) in the presence of concentrated sulfuric acid and butanol under reflux. After several days, the butyl ester of the desired product has formed which must then be hydrolysed. The long reaction times and the danger of dialkylation made it necessary to search for methods to prepare compounds of the general formula I under gentle conditions in better space-time yields.
Fremgangsmåten ifølge oppfinnelsen består nå i at The method according to the invention now consists in that
det overraskende lykkes å redusere acylaminogruppen ved tilsetning av diboran eller ved tilsetning av komplekse borhydrider i nærvær av Lewis-syrer uten å endre de andre grupper i molekylet. Herved fåes høye utbytter. Etter avsluttet reduksjon lar 3-alkylamino-5-sulfamylbenzosyrene seg eventuelt sette i frihet fra karboksylsyreestrene ved hydrolyse, hydrogenolyse eller elimineringsreaksjoner. it surprisingly succeeds in reducing the acylamino group by adding diborane or by adding complex borohydrides in the presence of Lewis acids without changing the other groups in the molecule. This results in high yields. After completion of the reduction, the 3-alkylamino-5-sulfamylbenzoic acids can optionally be set free from the carboxylic acid esters by hydrolysis, hydrogenolysis or elimination reactions.
De ifølge oppfinnelsen anvendte 3-acylamino-5-sulfa-mylbenzosyreederivater med formel II er tilgjengelige etter forskjellige fremgangsmåter, eksempelvis fra 3~amino-5-sulfamyl-benzosyrederivater med den generelle formel III: The 3-acylamino-5-sulfamylbenzoic acid derivatives of formula II used according to the invention are available by various methods, for example from 3-amino-5-sulfamylbenzoic acid derivatives of the general formula III:
hvori resten R^ har de angitte betydninger, idet man omsetter disse aminoforbindelser med til amiddannelse egnede karboksyl-syrederivater, som f.eks. karboksylsyreanhydrid eller karbok-sylsyrehalogenidene på vanlig måte. in which the residue R^ has the indicated meanings, as these amino compounds are reacted with carboxylic acid derivatives suitable for amide formation, such as e.g. carboxylic acid anhydride or the carboxylic acid halides in the usual way.
For acyleringen nødvendige aminoforbindelse med formel III er kjent fra litteraturen. Alkoksymetyl-, fenoksymetyl-og fenyltiometylsulfamylderivatene av 4-fenoksyforbindelser får man f.eks. ved omsetning av 3-nitro-^-fenoksy-5-sulfamyl-benzosyreestere med formaldehyd og alkohol og etterfølgende reduksjon av nitrogruppen. The amino compound of formula III required for the acylation is known from the literature. Alkoxymethyl, phenoxymethyl and phenylthiomethylsulfamyl derivatives of 4-phenoxy compounds are obtained, e.g. by reaction of 3-nitro-^-phenoxy-5-sulfamyl-benzoic acid esters with formaldehyde and alcohol and subsequent reduction of the nitro group.
3-aminobenzosyrederivatene med formel III kan fåes The 3-aminobenzoic acid derivatives of formula III can be obtained
og omsettes som fri syrer eller i form av deres estere. and are converted as free acids or in the form of their esters.
De tilsvarende 3-acylamino-benzosyrederivater med formel II reduseres nå etter fremgangsmåten ifølge oppfinnelsen med borhydrogen eller ved komplekse borhydrider i nærvær av Lewis-syrer. The corresponding 3-acylamino-benzoic acid derivatives of formula II are now reduced according to the method according to the invention with boron hydrogen or by complex boron hydrides in the presence of Lewis acids.
Derved kan de anvendes som fri karboksylsyrer. Det er imidlertid fordelaktig før reduksjonens begynnelse å overføre karbok-sylsyrene i et salt som ikke hindrer reduksjonen, som f.eks. et alkali- eller jordalkalisalt. For spesielt å få rene omsetningspro-dukter i høye utbytter er det spesielt fordelaktig å anvende 3-acylamino-5-sulfamyl-benzosyreestrene til reduksjon.'Thereby they can be used as free carboxylic acids. However, it is advantageous before the beginning of the reduction to transfer the carboxylic acids in a salt which does not prevent the reduction, such as e.g. an alkali or alkaline earth salt. In order to especially obtain pure conversion products in high yields, it is particularly advantageous to use the 3-acylamino-5-sulfamyl-benzoic acid esters for reduction.
Estrene lar seg fremstille etter kjente fremgangsmåter. Som ester har det spesielt vist seg egnet lavere alkylestere med 1 til 5 karbonatomer, som metylester, etylester eller n-pentylester, eventuelt i fenylkjernen med halogen, alkoksygrupper med 1-5 karbonatomer eller nitrogrupper substituert benzylester, som f.eks. benzylesteren eller p-metoksybenzylestere eller også t-butylesteren og benzhydrylesteren. The esters can be prepared according to known methods. Lower alkyl esters with 1 to 5 carbon atoms, such as methyl ester, ethyl ester or n-pentyl ester, optionally in the phenyl nucleus with halogen, alkoxy groups with 1-5 carbon atoms or nitro groups substituted benzyl ester, such as e.g. the benzyl ester or p-methoxybenzyl esters or also the t-butyl ester and the benzhydryl ester.
Som reduksjonsmiddel kommer det i betraktning forskjellige borhydrider, som f.eks. diboran. De kan innføres under tilsvarende beskyttelsesforholdsregler som f.eks. anvendelse av nitrogen som inertgass i reaksjonsblandingen. For reaksjons føringen er det enklere å oppta borhydrogenene, som f.eks. diboran i oppløsningsmidler og å anvende oppløsningen til reduksjon. Som oppløsningsmiddel egner det seg spesielt etere, f.eks. tetrahydrofuran eller dietylenglykoldimetyleter. Various borohydrides, such as e.g. diborane. They can be introduced under corresponding protective measures, such as e.g. use of nitrogen as an inert gas in the reaction mixture. For the conduct of the reaction, it is easier to take up the boron hydrogens, which e.g. diborane in solvents and using the solution for reduction. As a solvent, ethers are particularly suitable, e.g. tetrahydrofuran or diethylene glycol dimethyl ether.
Det for reduksjonen anvendte diboran kan fremstilles The diborane used for the reduction can be prepared
på forskjellige måter, f.eks. ved omsetning av bortriklorid med LiAlH^ i henhold til ligningen in different ways, e.g. by reaction of boron trichloride with LiAlH^ according to the equation
eller fra tetraalkylammoniumboranat og alkylhalogenider (Tetrahedron Letters 1972 , 3173). or from tetraalkylammonium boranate and alkyl halides (Tetrahedron Letters 1972, 3173).
Alternativt oppnår man den samme reduksjon av 3~acyl-aminoforbindelsene med formel II, når man lar komplekse borhydrider innvirke i nærvær av Lewis-syrer. Alternatively, the same reduction of the 3-acyl-amino compounds of formula II is achieved when complex borohydrides are allowed to act in the presence of Lewis acids.
De ved denne reduksjonsmetode anvendte komplekse hydrider av bor er f.eks. alkaliboranater, som litiumborhydrid, natriumborhydrid eller kaliumborhydrid eller jordalkaliboranater, som kalsiumborhydrid, men også sinkborhydrid eller aluminiumborhydrid. Disse borhydrider reduserer ved tilsetning av Lewis-syrer 3-acyl-aminogruppene til 3-alkylaminogrupper uten vesentlig å angripe karbcksylsyreesterfunksjonen. The complex hydrides of boron used in this reduction method are e.g. alkali boranates, such as lithium borohydride, sodium borohydride or potassium borohydride or alkaline earth boranates, such as calcium borohydride, but also zinc borohydride or aluminum borohydride. By adding Lewis acids, these borohydrides reduce the 3-acyl-amino groups to 3-alkylamino groups without significantly attacking the carboxylic acid ester function.
Som Lewis-syrer innen oppfinnelsens ramme gjelder spesielt aluminiumklorid, titantetraklorid, tinntetraklorid, kobolt-II-klorid, jern-III-klorid, kvikksølv-I-klorid, sinkklorid og bor-trifluorid og dets addukter, som eksempelvis bortrifluorideterat. Herved består den mulihet at ved omsetningen av bortrifluorideteratet, f.eks. med natriumborhydrid kan diboran oppstå in situ, (sammenlign Pieser, Fieser: Reagents for Organic Synthesis, John Wiley and Sons, Inc.,'New York, Vol. 1, side 199). As Lewis acids within the scope of the invention apply in particular aluminum chloride, titanium tetrachloride, tin tetrachloride, cobalt II chloride, iron III chloride, mercury I chloride, zinc chloride and boron trifluoride and its adducts, such as boron trifluoride etherate. Hereby, there is the possibility that during the conversion of the boron trifluoride etherate, e.g. with sodium borohydride, diborane can occur in situ, (compare Pieser, Fieser: Reagents for Organic Synthesis, John Wiley and Sons, Inc.,' New York, Vol. 1, page 199).
For oppnåelse av en høy omsetning må man anvende reduk-sjonsmidlet i minst støkiometrisk mengde. Det har imidlertid vist seg gunstig å anvende mer enn den støkiometriske mengde av reduksjons-midlet. Mengden av tilsatt Lewis-syre kan være lik, det viser seg imidlertid at det ofte er tilstrekkelig å anvende Lewis-syren i støkiometrisk mengde referert til stoffet som skal reduseres og å anvende de komplekse borhydrider i overskudd. To achieve a high turnover, the reducing agent must be used in at least a stoichiometric amount. However, it has proved advantageous to use more than the stoichiometric amount of the reducing agent. The amount of added Lewis acid can be equal, however, it turns out that it is often sufficient to use the Lewis acid in a stoichiometric amount referred to the substance to be reduced and to use the complex borohydrides in excess.
Således oppnår man meget gunstige resultater, når man eksempelvis ved titantetraklorid tilsetter fire ganger den støkiome-triske mengde av NaBH^, mens ved anvendelse av bortrifluorideterat natriumborhydridet kan anvendes i støkiometrisk mengde. Thus, very favorable results are obtained when, for example, with titanium tetrachloride, four times the stoichiometric amount of NaBH 2 is added, while when using boron trifluoride etherate, the sodium borohydride can be used in a stoichiometric amount.
En oversikt over de ved reaksjonen av NaBH^ med Lewis-syrer mulige komplekser er f.eks. angitt i Fieser/Fieser: Reagents for Organic Synthesis, John Wiley and Sons Inc., New York, spesielt volum I, side 1053 - 1054, An overview of the complexes possible by the reaction of NaBH^ with Lewis acids is e.g. given in Fieser/Fieser: Reagents for Organic Synthesis, John Wiley and Sons Inc., New York, especially Volume I, pages 1053 - 1054,
volum II, side 430 - 431, volume II, pages 430 - 431,
volum III, side 264 - 265. volume III, pages 264 - 265.
For bedre reaksjonsføring er det fordelaktig å gjennom-føre reaksjonen i et oppløsningsmiddel. Som oppløsningsmidler kommer det i betraktning slike, som ikke uheldig påvirker reduksjonen, eksempelvis etere som tetrahydrofuran eller dietylenglykoldimetyleter. Oppløsningsmidlet, hvori reduksjonen kan gjennomføres kan være det samme som det, hvori borhydrogenet er oppløst, kan imidlertid avvike herfra. Reduksjonen kan gjennomføres innen et vidt temperaturområde. Reaksjonstemperaturene avhenger av hvilke stoffklasse (syre eller ester) og hvilket reduksjonsmiddel som anvendes. Som spesielt fordelaktig har det vist seg at reduksjonen kan gjennomføres ved værelsestemperatur eller svakt forhøyet temperatur. Tar man lengere reaksjonstider med på kjøpet, så lar reduksjonen seg også gjennomføre kaldt. Reaksjonsvarigheten avhenger sterkt av de anvendte reaksjonskomponenter, av mengdene som skal omsettes og den valgte temperatur. For better reaction progress, it is advantageous to carry out the reaction in a solvent. As solvents, those which do not adversely affect the reduction, for example ethers such as tetrahydrofuran or diethylene glycol dimethyl ether, are taken into consideration. The solvent in which the reduction can be carried out may be the same as that in which the boron hydrogen is dissolved, but may differ from this. The reduction can be carried out within a wide temperature range. The reaction temperatures depend on which substance class (acid or ester) and which reducing agent is used. As particularly advantageous, it has been shown that the reduction can be carried out at room temperature or a slightly elevated temperature. If longer reaction times are included in the purchase, the reduction can also be carried out cold. The reaction duration depends strongly on the reaction components used, on the quantities to be reacted and on the selected temperature.
En foretrukket utførelses form av fremgangsmåten ifølge oppfinnelsen består i å ha acylamino-sulfamylbenzosyrederivatene med formel II i et inert oppløsningsmiddel og å tildryppe en oppløsning av borhydrogen i samme eller et annet oppløsningsmiddel ved yærelses-temperatur. Por aksellerering av reaksjonen kan reaksjonen også gjennomføres ved høyere temperaturer. Det har vist seg fordelaktig etter avslutning av tilsetningen å oppvarme ca. 1 time ved 60-80°C. A preferred embodiment of the method according to the invention consists in having the acylamino-sulfamylbenzoic acid derivatives of formula II in an inert solvent and adding dropwise a solution of boron hydrogen in the same or another solvent at room temperature. Due to acceleration of the reaction, the reaction can also be carried out at higher temperatures. It has proven beneficial after the addition has been completed to heat approx. 1 hour at 60-80°C.
En annen utførelsesform består i å ha stoffet som skal reduseres sammen med det komplekse borhydrid og å tilsette Lewis-syren ved værelsestemperatur. Som spesielt lett disponerbart komplekst borhydrid kommer det spesielt til anvendelse natriumborhydrid, som aktiveres med de allerede nevnte Lewis-syrer, som f.eks. bortrifluorid-. et erat, aluminiumklorid eller titantetraklorid. Ved anvendelse av komplekse borhydrider er det igjen spesielt gunstig å ha stoffet som skal reduseres med Lewis-syren og først deretter å tildryppe det komplekse borhydrid som befinner seg i oppløsning. Another embodiment consists in having the substance to be reduced together with the complex borohydride and adding the Lewis acid at room temperature. Sodium borohydride, which is activated with the already mentioned Lewis acids, such as e.g. boron trifluoride-. et erate, aluminum chloride or titanium tetrachloride. When using complex borohydrides, it is again particularly advantageous to have the substance to be reduced with the Lewis acid and only then to add the complex borohydride which is in solution.
Por oppnåelse av en hurtig omsetning er det fordelaktig etter tilsetningens avslutning å oppvarme ca. 1 - 4 timer ved 50 - 150°C, fortrinnsvis 50 - 70OC. In order to achieve a rapid conversion, it is advantageous after the end of the addition to heat approx. 1 - 4 hours at 50 - 150°C, preferably 50 - 70°C.
Har man eksempelvis for reduksjonen■anvendt en acyl-aminobenzosyreester med formel II, så viser det etter oppvarmning et kontrolltynnsjiktkromatogram dannelsen av den ønskede 3-alkylamino-5-sulfarnylbenzosyreester. Sluttproduktets isolering kan foregå på forskjellige måter, alt etter om det som sluttprodukt fra reduksjonen ønskes den fri syre eller den tilsvarende 3-alkylamino-sulfamylbenzo-syreester. If, for example, an acyl-aminobenzoic acid ester of formula II has been used for the reduction, then after heating, a control thin-layer chromatogram shows the formation of the desired 3-alkylamino-5-sulfanylbenzoic acid ester. The isolation of the end product can take place in different ways, depending on whether the end product from the reduction is the free acid or the corresponding 3-alkylamino-sulfamylbenzoic acid ester.
En foretrukket opparbeidelsesmetode består i å befri oppløsningen av reaksjonsproduktet ved tilsetning av mindre mengder av en syre for eventuelt ennu tilstedeværende reduksjonsmiddel og deretter å utfelle 3_alkylamino-5-sulfamylbenzosyreestere ved tilsetning av et ikke-oppløsningsmiddel. Ved anvendelse av dietylenglykoldi-metylfcter kan man som ikke oppløsningsmiddel, spesielt gunstig tilsette vann. De dannede 3-alkylamino-benzosyreestere utkrystalliserer for det meste i høy renhet omtrent kvantitativt. A preferred work-up method consists in freeing the solution of the reaction product by adding small amounts of an acid for any reducing agent still present and then precipitating 3-alkylamino-5-sulfamylbenzoic acid esters by adding a non-solvent. When using diethylene glycol dimethyl ester, water can be added as a non-solvent, particularly advantageously. The 3-alkylamino-benzoic acid esters formed mostly crystallize in high purity approximately quantitatively.
Estrene lar seg deretter, hvis ønskelig, ved hydrolyse, spesielt imidlertid ved hydrogenolyse eller ved elimineringsreaksjoner overføre i de fri N-alkylamino-sulfamylbenzosyrer med formel I The esters can then, if desired, be converted by hydrolysis, especially by hydrogenolysis or by elimination reactions, into the free N-alkylamino-sulfamylbenzoic acids of formula I
(R<3> = H). (R<3> = H).
En annen fremstilling av 3-alkylaminosulfamylbenzosyrene med formel I (R<3> = H) består i at man inndamper reaksjonsblandingen etter spaltning av overskytende reduksjonsmiddel delvis, .tilsetter fortynnet base og eventuelt oppvarmer i kort tid. Som base tjener f.eks. natronlut. 3-alkylamino-5-sulfamylbenzosyrene lar seg isolere som salter, man kan imidlertid også hvis ønsket ved surgjøring oppnå Another preparation of the 3-alkylaminosulfamylbenzoic acids of formula I (R<3> = H) consists in evaporating the reaction mixture after partial cleavage of the excess reducing agent, adding diluted base and possibly heating for a short time. As a base serves e.g. baking soda. The 3-alkylamino-5-sulfamylbenzoic acids can be isolated as salts, however, if desired, they can also be obtained by acidification
de fri syrer med formel I (R<3> = H).. the free acids of formula I (R<3> = H)..
Ved det meget glatte forløp av acyleringen av aminofor-bindelsene med formel III og den etterfølgende reduksjon av 3~acyl-aminosulfamylbenzosyrederivat med formel II fåes 3-alkylamino-sulfamylbenzosyrederivatene med formel I i høy renhet og høyt romtids-utbytte. Ved den bekvemme gjenvinning av de til reaksjonsføringen anvendte oppløsningsmidler og de små mengder biprodukter er denne fremgangsmåte spesielt miljøvennlig. By the very smooth progress of the acylation of the amino compounds of formula III and the subsequent reduction of 3-acyl-aminosulfamylbenzoic acid derivative of formula II, the 3-alkylamino-sulfamylbenzoic acid derivatives of formula I are obtained in high purity and high space-time yield. Due to the convenient recycling of the solvents used for carrying out the reaction and the small amounts of by-products, this method is particularly environmentally friendly.
Ved fremgangsmåten ifølge oppfinnelsen kan det foruten de allerede kjente forbindelser med formel I fortrinnsvis fremstilles følgende: 3-butylamino-4-fenoksy-5-sulfamy1-benzosyre-etylester 3-butylamino-4-fenoksy-5-sulfamyl-benzosyre-n-pentylester 3-butylamino-4-fenoksy-5-sulfamyl-benzosyre-n-heksylester 3-butylamino-4-fenoksy-5-sulfamyl-benzosyre-t-butylester 3-butylamino-4-fenoksy-5-sulfamyl-benzosyre-benzylester 3-butylamino-4-fenoksy-5-sulfamyl-benzosyre-p-metoksybenzylest er 3-butylamino-4-fenoksy-5-sulfamyl-benzosyre-benzhydrylester 3-butylamino-4-fenoksy-5-sulfamyl-benzosyre-tetrahydropyranylester 3-butylamino-4 -fenoksy-5-sulfamyl-benzosyre-pivaloy loksy met yles ter 5-metoksyrnet<y>lsulfam<y>l-3-but<y>lamino-4-fenoksy-benzosyre-t-butylester 5-metoksymetylsulfamy1-3-butylamino-4-fenoksy-benzosyre-benzylester 5-metoksymetylsulfamyl-3-butylamino-4-fenoksy-benzosyre-benzhydrylester 5-metoksymetylsulfamyl-3-butylamino-4-fenoksy-benzosyre-p-metoksy-benzylester With the method according to the invention, in addition to the already known compounds of formula I, the following can preferably be prepared: 3-butylamino-4-phenoxy-5-sulfamy-1-benzoic acid ethyl ester 3-butylamino-4-phenoxy-5-sulfamyl-benzoic acid-n-pentyl ester 3-Butylamino-4-phenoxy-5-sulfamyl-benzoic acid n-hexyl ester 3-Butylamino-4-phenoxy-5-sulfamyl-benzoic acid t-butyl ester 3-Butylamino-4-phenoxy-5-sulfamyl-benzoic acid benzyl ester 3 -butylamino-4-phenoxy-5-sulfamyl-benzoic acid p-methoxybenzyl ester is 3-butylamino-4-phenoxy-5-sulfamyl-benzoic acid benzhydryl ester 3-butylamino-4-phenoxy-5-sulfamyl-benzoic acid tetrahydropyranyl ester 3-butylamino -4-phenoxy-5-sulfamyl-benzoic acid pivaloyloxy methyl ester 5-methoxylsulfamyl-3-but<y>lamino-4-phenoxy-benzoic acid t-butyl ester 5-methoxymethylsulfamy1-3 -butylamino-4-phenoxy-benzoic acid benzyl ester 5-methoxymethylsulfamyl-3-butylamino-4-phenoxy-benzoic acid benzhydryl ester 5-methoxymethylsulfamyl-3-butylamino-4-phenoxy-benzoic acid p-methoxy-benzyl ester
5-metoksymetylsulfamyl-3~butylamino-4-fenoksy-benzosyre-p-nitro-benzylester 5-Methoxymethylsulfamyl-3-butylamino-4-phenoxy-benzoic acid p-nitro-benzyl ester
5-butoksymetylsulfamyl-3-butylamino-4-fenoksy-benzosyre-t-butylester 5-butoksymetylsulfamyl-3-butylamino-4-fenoksy-benzosyre-benzylester 5-butoksymetylsulfamyl-3-butylamino-4-fenoksy-benzosyre-benzhydrylester 5-butoksymetylsulfamyl-3-butylamino-4-fenoksy-benzosyre-p-metoksy-benzylester 5-butoksyrnetyl sulfamyl-3-butylamino-4-fenoksy-benzosyre-p-nitrobenzyl-ester 5-butoxymethylsulfamyl-3-butylamino-4-phenoxy-benzoic acid t-butyl ester 5-butoxymethylsulfamyl-3-butylamino-4-phenoxy-benzoic acid benzyl ester 5-butoxymethylsulfamyl-3-butylamino-4-phenoxy-benzoic acid benzhydryl ester 5-butoxymethylsulfamyl -3-butylamino-4-phenoxy-benzoic acid p-methoxy-benzyl ester 5-butoxymethyl sulfamyl 3-butylamino-4-phenoxy-benzoic acid p-nitrobenzyl ester
5-decyloksymetylsulfamyl-3-butylamino-4-fenoksy-benzosyre-t-butylester 5-decyloksymetylsulfamyl-3-butylamino-4-fenoksy-benzosyre-benzylester 5-decyloksymetylsulfamyl-3-butylamino-4-fenoksy-benzosyre-benzhydryl-ester 5-decyloxymethylsulfamyl-3-butylamino-4-phenoxy-benzoic acid t-butyl ester 5-decyloxymethylsulfamyl-3-butylamino-4-phenoxy-benzoic acid benzyl ester 5-decyloxymethylsulfamyl-3-butylamino-4-phenoxy-benzoic acid benzhydryl ester
5-decyloksymetylsulfamyl-3-butylamino-4-fenoksy-benzosyre-p-metoksy-benzylester 5-decyloxymethylsulfamyl-3-butylamino-4-phenoxy-benzoic acid p-methoxy-benzyl ester
5-decyloksymetylsulfamy1-3-butylamino-4-fenoksy-benzosyre-p-nitro-benzylester 5-decyloxymethylsulfamy1-3-butylamino-4-phenoxy-benzoic acid p-nitro-benzyl ester
5-metylsulfamy1-3-butylamino-4-fenoksy-benzosyrebenzylester 5-butylsulfamy1-3-butylamino-4-fenoksy-benzosyre-t-butylester 5-benzylsulfamyl-3-butylamino-4-fenoksy-benzosyremetylester 5-dimetylsulfamy1-3-butylamino-4-fenoksy-benzosyrebenzhydrylester 5-fenylsulfamy1-3-butylamino-4-fenoksy-benzosyre-n-heksylester. 5-methylsulfamy1-3-butylamino-4-phenoxy-benzoic acid benzyl ester 5-butylsulfamy1-3-butylamino-4-phenoxy-benzoic acid t-butyl ester 5-benzylsulfamyl-3-butylamino-4-phenoxy-benzoic acid methyl ester 5-dimethylsulfamy1-3-butylamino -4-phenoxy-benzoic acid benzhydryl ester 5-phenylsulfamy1-3-butylamino-4-phenoxy-benzoic acid n-hexyl ester.
Istedenfor de ovenfor anførte fremgangsmåteprodukter kommer det også i betraktning de hvori det istedenfor "-4-fenoksy" består substituerte 4-fenoksy-grupper, som -4'-klorfenoksy-, -4'-metylfenoksy-, -4'-metoksyfenoksy-, -4'-aminofenoksy-, -4'-nitrofenoksy-, -4'-etylaminofenoksy-, -2',4'-dimetylfenoksy-, -3',4'-dimetoksyfenoksy-, -2',4'-dimetylfenoksy-, -3',4'-dimetoksyfenoksy-, samt samtlige fri karboksylsyrer av de overnevnte benzosyreestere. Instead of the process products listed above, those in which instead of "-4-phenoxy" consist of substituted 4-phenoxy groups, such as -4'-chlorophenoxy-, -4'-methylphenoxy-, -4'-methoxyphenoxy-, -4'-aminophenoxy-, -4'-nitrophenoxy-, -4'-ethylaminophenoxy-, -2',4'-dimethylphenoxy-, -3',4'-dimethoxyphenoxy-, -2',4'-dimethylphenoxy- , -3',4'-dimethoxyphenoxy-, as well as all free carboxylic acids of the above-mentioned benzoic acid esters.
Ved fremgangsmåten ifølge oppfinnelsen kan det videre fortrinnsvis fremstilles følgende forbindelser med den generelle formel I : 3-cyklopropylmetylamino-4-fenoksy-5-sulfamyl-benzosyre, 3-cyklopropyImetylamino-4-(4'-klorfenoksy)-sulfamyl-benzosyre, 3-cyklopropylmetylamino-4-(4'-metylfenoksy)-sulfamyl-benzosyre, 3-cyklopropylmetylamino-4 -(4'-etylaminofenoksy)-sulfamyl-benzosyre, 3-cyklopropyImetylamino-4-(4<1->aminofenoksy)-sulfamyl-benzosyre, 3-cyklopropylmetylamino-4-(4'-metoksyfenoksy)-sulfamyl-benzosyre, 3-cyklopropylmetylamino-4-(4'-hydroksyfenoksy)-sulfamyl-benzosyre, 3-cyklopropylmetylamino-4-(4'-nit rofenoksy)-sulfamyl-benzosyre, 3-cyklopropylmetylamino-4 -(2',4'-dimetylfenoksy)-sulfamyl-benzosyre, 3-cyklopropylmetylamino-4-(3<1>,4'-dimetoksyfenoksy)-sulfamyl-benzosyre, 3-cyklopropylmetylamino-4 -(3'-trifluorfenoksy)-sulfamyl-benzosyre, 3-cyklopropylmetylamino-4-fenyltio-5-sulfamyl-benzosyre, 3-cyklopropylmetylamino-4-benzy1-5-sulfamyl-benzosyre, 3-cyklobutylmetylamino-4-fenoksy-5-sulfamyl-benzosyre, 3-cyklobutylmetylamino-4-fenyltio-5-sulfamyl-benzosyre, 3-cyklobutylmetylamino-4-benzyl-5-sulfamyl-benzosyre, 3-fenyletylamino-4-fenoksy-5-sulfamyl-benzosyre, 3-fenyletylamino-4-(4'-klorfenoksy)-sulfamyl-benzosyre, 3-fenyletylamino-4-(4'-metylfenoksy)-sulfamyl-benzosyre, 3-fenyletylamino-4-(4'-metoksyfenoksy)-sulfamyl-benzosyre, 3-fenyletylamino-4-(4'-etylaminofenoksy)-sulfamyl-benzosyre, 3-fenyletylamino-4-(4'-aminofenoksy)-sulfamyl-benzosyre, 3-fenyletylamino-4-(2',4'-dimetylfenoksy)-sulfamyl-benzosyre, 3-fenyletylamino-4-fenyltio-5-sulfamyl-benzosyre, 3-fenyletylamino-4-benzyl-5-sulfamyl-benzosyre, 3-benzylamino-4-fenoksy-5-sulfamyl-benzosyre, With the method according to the invention, the following compounds with the general formula I can also preferably be prepared: 3-cyclopropylmethylamino-4-phenoxy-5-sulfamyl-benzoic acid, 3-cyclopropylmethylamino-4-(4'-chlorophenoxy)-sulfamyl-benzoic acid, 3- cyclopropylmethylamino-4-(4'-methylphenoxy)-sulfamyl-benzoic acid, 3-cyclopropylmethylamino-4-(4'-ethylaminophenoxy)-sulfamyl-benzoic acid, 3-cyclopropylmethylamino-4-(4<1->aminophenoxy)-sulfamyl-benzoic acid , 3-cyclopropylmethylamino-4-(4'-methoxyphenoxy)-sulfamyl-benzoic acid, 3-cyclopropylmethylamino-4-(4'-hydroxyphenoxy)-sulfamyl-benzoic acid, 3-cyclopropylmethylamino-4-(4'-nitrophenoxy)-sulfamyl -benzoic acid, 3-cyclopropylmethylamino-4-(2',4'-dimethylphenoxy)-sulfamyl-benzoic acid, 3-cyclopropylmethylamino-4-(3<1>,4'-dimethoxyphenoxy)-sulfamyl-benzoic acid, 3-cyclopropylmethylamino-4 -(3'-trifluorophenoxy)-sulfamyl-benzoic acid, 3-cyclopropylmethylamino-4-phenylthio-5-sulfamyl-benzoic acid, 3-cyclopropylmethylamino-4-benzyl1-5-sulfamyl-benzoic acid, 3-cyclobutylmethylamino-4-phenox γ-5-sulfamyl-benzoic acid, 3-cyclobutylmethylamino-4-phenylthio-5-sulfamyl-benzoic acid, 3-cyclobutylmethylamino-4-benzyl-5-sulfamyl-benzoic acid, 3-phenylethylamino-4-phenoxy-5-sulfamyl-benzoic acid, 3-phenylethylamino-4-(4'-chlorophenoxy)-sulfamyl-benzoic acid, 3-phenylethylamino-4-(4'-methylphenoxy)-sulfamyl-benzoic acid, 3-phenylethylamino-4-(4'-methoxyphenoxy)-sulfamyl-benzoic acid , 3-phenylethylamino-4-(4'-ethylaminophenoxy)-sulfamyl-benzoic acid, 3-phenylethylamino-4-(4'-aminophenoxy)-sulfamyl-benzoic acid, 3-phenylethylamino-4-(2',4'-dimethylphenoxy) -sulfamyl-benzoic acid, 3-phenylethylamino-4-phenylthio-5-sulfamyl-benzoic acid, 3-phenylethylamino-4-benzyl-5-sulfamyl-benzoic acid, 3-benzylamino-4-phenoxy-5-sulfamyl-benzoic acid,
3-benzylamino-4-fenyltio-5~sulfamyl-benzosyre, 3-benzylamino-4-phenylthio-5-sulfamyl-benzoic acid,
3-benzylamino-4-benzyl-5-sulfamyl-benzosyre, 3-benzylamino-4-benzyl-5-sulfamyl-benzoic acid,
3-furfurylamino-4-fenoksy-5-sulfamyl-benzosyre, 3-furfurylamino-4-fenyltio-5-sul famyl-benzosyre, 3-furfurylamino-4-benzyl-5-sulfamyl-benzosyre, 3-furfurylamino-4-phenoxy-5-sulfamyl-benzoic acid, 3-furfurylamino-4-phenylthio-5-sul famil-benzoic acid, 3-furfurylamino-4-benzyl-5-sulfamyl-benzoic acid,
3-(2-metoksyetylamino)-4-fenoksy-5-sulfamy1-benzosyre, 3-(2-metoksyetylamino)-4-fenyltio-5-sulfamyl-benzosyre, 3-(2-metoksyetylamino)-4-benzyl-5-sulfamyl-benzosyre, 3-(2-metyltioetylamino)-4-fenoksy-5-sul famy1-benzosyre, 3-(2-metyltioetylamino)-4-fenyltio-5-sulfamy1-benzosyre, 3-(2-metyltioetylamino)-4-benzy1-5-sulfamy1-benzosyre, 3~(2-metylaminoetylamino)-4-fenoksy-5-sulfamy1-benzosyre, 3-(2-metylaminoetylamino)-4-fenyltio-5-sulfamy1-benzosyre, 3-(2-metylaminoetylamino)-4-benzyl-5-sulfamy1-benzosyre, 3-(4-hydroksybutylamino)-4-fenoksy-5-sulfamyl-benzosyre, 3-(4-hydroksybutylamino)-4-fenyltio-5-sulfamyl-benzosyre, 3-(4-hydroksybutylamino)-4-benzyl-5-sulfamyl-benzosyre, 3~(3-hydroksypropylamino)-4-fenoksy-5-sul famy1-benzosyre, 3-(3-hydroksypropylamino)-4-fenyltio-5-sulfamy1-benzosyre, 3-(3-hydroksypropylamino)-4-benzyl-5-sulfamy1-benzosyre, 3-(4-klor-butylamino)-4-fenoksy-5-sulfamy1-benzosyre-metylester, 3~(4-klor-butylamino)-4-fenyltio-5-sulfamyl-benzosyre-metylester, 3-(4-klor-butylamino)-4-benzy1-5-sulfamy1-benzosyremetylester, 3-(3-klor-propylamino)-4-fenoksy-5-sul famy1-benzosyremetylester, 3-(3-klor-propylamino)-4-fenyltio-5-sulfamy1-benzosyremetylest er, 3-(3-klor-propylamino)-4-benzyl-5-sulfamyl-benzosyremetylester, 3-(2-klor-etylamino)-4-fenoksy-5-sulfamy1-benzosyrernetylester, 3-(2-klor-etylamino)-4-fenyltio-5-sulfamyl-benzosyremetylester, 3-(2-klor-etylamino)-4-benzyl-5-sul famy1-benzosyremetylester. 3-(2-Methoxyethylamino)-4-phenoxy-5-sulfamy1-benzoic acid, 3-(2-methoxyethylamino)-4-phenylthio-5-sulfamyl-benzoic acid, 3-(2-methoxyethylamino)-4-benzyl-5- sulfamylbenzoic acid, 3-(2-methylthioethylamino)-4-phenoxy-5-sulfamy1-benzoic acid, 3-(2-methylthioethylamino)-4-phenylthio-5-sulfamy1-benzoic acid, 3-(2-methylthioethylamino)-4 -benzy1-5-sulfamy1-benzoic acid, 3~(2-methylaminoethylamino)-4-phenoxy-5-sulfamy1-benzoic acid, 3-(2-methylaminoethylamino)-4-phenylthio-5-sulfamy1-benzoic acid, 3-(2- methylaminoethylamino)-4-benzyl-5-sulfamy1-benzoic acid, 3-(4-hydroxybutylamino)-4-phenoxy-5-sulfamyl-benzoic acid, 3-(4-hydroxybutylamino)-4-phenylthio-5-sulfamyl-benzoic acid, 3 -(4-hydroxybutylamino)-4-benzyl-5-sulfamyl-benzoic acid, 3~(3-hydroxypropylamino)-4-phenoxy-5-sulfamy1-benzoic acid, 3-(3-hydroxypropylamino)-4-phenylthio-5- sulfamy1-benzoic acid, 3-(3-hydroxypropylamino)-4-benzyl-5-sulfamy1-benzoic acid, 3-(4-chloro-butylamino)-4-phenoxy-5-sulfamy1-benzoic acid methyl ester, 3~(4-chloro -butylamino)-4-phenylthio-5-sulfamyl-benzoic acid methyl ester, 3-(4-chloro-butyl amino)-4-benzyl-5-sulfamy1-benzoic acid methyl ester, 3-(3-chloro-propylamino)-4-phenoxy-5-sulfami1-benzoic acid methyl ester, 3-(3-chloro-propylamino)-4-phenylthio-5- sulfamy1-benzoic acid methyl ester, 3-(3-chloro-propylamino)-4-benzyl-5-sulfamyl-benzoic acid methyl ester, 3-(2-chloro-ethylamino)-4-phenoxy-5-sulfamy1-benzoic acid methyl ester, 3-(2- chloro-ethylamino)-4-phenylthio-5-sulfamyl-benzoic acid methyl ester, 3-(2-chloro-ethylamino)-4-benzyl-5-sulfamyl-benzoic acid methyl ester.
Fremstillingseksempler: Production examples:
Eksempel 1^Example 1^
Metyl- 3- n- butyrylamino- 4- fenoksy- 5- sulfamyl- benzoat. Methyl- 3- n- butyrylamino- 4- phenoxy- 5- sulphamyl- benzoate.
Fremgangsmåte A: Procedure A:
Til den kokende oppløsning av 16 g metyl-3-amino-4-fenoksy-5-sulfamyl-benzoat og 5 ml pyridin i 100 ml vannfri dioksan drypper man langsomt og under god omrøring en oppløsning av 9 ml smørsyreklorid i 100 ml aceton. Etter ca. 4 timer inndamper man reaksjonsblandingen på rotasjonsfordamper, opptar det gjenblivende oljeaktige produkt med litt metanol og drypper denne oppløsning under kraftig omrøring i en blanding av isvann og 2 N saltsyre. Metyl-3-n-butyrylamino-4-fenoksy-5-sulfamyl-benzoat faller ut med meget godt utbytte i hvite fnokker. Smeltepunkt l87-194°C. To the boiling solution of 16 g of methyl-3-amino-4-phenoxy-5-sulfamyl-benzoate and 5 ml of pyridine in 100 ml of anhydrous dioxane, a solution of 9 ml of butyric acid chloride in 100 ml of acetone is added slowly and with good stirring. After approx. After 4 hours, the reaction mixture is evaporated on a rotary evaporator, the remaining oily product is taken up with a little methanol and this solution is dripped with vigorous stirring into a mixture of ice water and 2 N hydrochloric acid. Methyl-3-n-butyrylamino-4-phenoxy-5-sulfamyl-benzoate precipitates in very good yield in white flakes. Melting point l87-194°C.
Etter omkrystallisering fra metanol eller etanol får After recrystallization from methanol or ethanol obtains
man et smeltepunkt på 195-197°C. one a melting point of 195-197°C.
Fremgangsm åte B: Procedure B:
Til den kokende blanding av 3,3 g metyl~3-amino-4-fenoksy-5-sulfamyl-benzoat og 3 g godt pulverisert kaliumkarbonat i 100 ml aceton drypper man under kraftig omrøring 2 ml smørsyreklorid i 25 ml aceton langsomt. Etter 3 timer under tilbakeløp opparbeider man som ved fremgangsmåte A. To the boiling mixture of 3.3 g of methyl~3-amino-4-phenoxy-5-sulfamyl-benzoate and 3 g of well-pulverized potassium carbonate in 100 ml of acetone, 2 ml of butyric acid chloride in 25 ml of acetone are slowly added dropwise with vigorous stirring. After 3 hours under reflux, work up as in method A.
Fremgangsmåte C: Method C:
Til oppløsningen av 10 g 3-n-butyrylamino-r4-fenoksy-5-sulfamyl-benzosyre i 100 ml THF drypper man i overskudd en eterisk oppløsning av diazometan. Man oppvarmer kort til kokning og spalter overskytende diazometan ved tilsetning av noen dråper iseddik. Oppløs-ningen inndampes og det gjenblivende metyl-3-n-butyrylamino-4-fenoksy-5-sulfamy1-benzoat omkrystalliseres fra metanol eller etanol.^To the solution of 10 g of 3-n-butyrylamino-r4-phenoxy-5-sulfamyl-benzoic acid in 100 ml of THF, an ethereal solution of diazomethane is added dropwise in excess. Heat briefly to boiling and split excess diazomethane by adding a few drops of glacial acetic acid. The solution is evaporated and the remaining methyl-3-n-butyrylamino-4-phenoxy-5-sulfamy1-benzoate is recrystallized from methanol or ethanol.^
Eksempel 2. Example 2.
Metyl- 3- n- butylamino- 4- fenoksy- 5- sulfamy1- benzoat^ Methyl- 3- n- butylamino- 4- phenoxy- 5- sulfamy1- benzoate^
Fremgangsmåte A: Procedure A:
Til en oppløsning av 559 g mety1-3-n-butyrylamino-4 - fenoksy-5-sulfamyl-benzoat og 1 g natriumtetrahydridoborat i 200 ml diglyme dryppes under omrøring en oppløsning av 4,55 g bortrifluorid-eteraddukt i 50 ml diglyme. Deretter oppvarmer man reaksjonsblandingen i 1 time ved 80-90°C. Etter avkjøling tilsetter man 15 ml med gassformet klorhydrogen mettet metanol og omrører ennu 1 time. Ved tilsetning av vann til den varme for overskytende klorhydrogen befridde oppløsning utkrystalliserer praktisk talt rent og i meget godt utbytte (80 - 90$) metyl-3-n-butylamino-4-fenoksy-5-sulfamyl-benzoat av smeltepunkt 146°C. To a solution of 559 g of methyl 1-3-n-butyrylamino-4-phenoxy-5-sulfamyl-benzoate and 1 g of sodium tetrahydridoborate in 200 ml of diglyme, a solution of 4.55 g of boron trifluoride ether adduct in 50 ml of diglyme is added dropwise while stirring. The reaction mixture is then heated for 1 hour at 80-90°C. After cooling, 15 ml of gaseous hydrogen chloride saturated with methanol are added and stirred for another 1 hour. When water is added to the warm solution freed from excess hydrogen chloride, methyl-3-n-butylamino-4-phenoxy-5-sulfamyl-benzoate of melting point 146°C crystallizes practically pure and in very good yield (80 - 90$).
Etter omkrystallisering fra metanol: Smeltepunkt 149 - 150°C. Reaksjonen lar seg også med godt resultat gjennomføre i , tetrahydrofuran. After recrystallization from methanol: Melting point 149 - 150°C. The reaction can also be carried out with good results in tetrahydrofuran.
Fremgangsmåte B: Method B:
Til en oppløsning av 4 g metyl-3_n-butyrylamino-4-fenoksy-5-sulfamyl-benzoat og 1,2 g natriumtetrahydridoborat i 100 ml diglyme drypper man langsomt og under omrøring en oppløsning av 1,3 g aluminiumtriklorid i 50 ml diglyme. Blandingen oppvarmes ca. 1 time ved 60 - 80°C og deretter spaltes overskytende reduksjonsmiddel ved tilsetning av 2 N eddiksyre. To a solution of 4 g of methyl-3_n-butyrylamino-4-phenoxy-5-sulfamyl-benzoate and 1.2 g of sodium tetrahydridoborate in 100 ml of diglyme, a solution of 1.3 g of aluminum trichloride in 50 ml of diglyme is added slowly and with stirring. The mixture is heated approx. 1 hour at 60 - 80°C and then excess reducing agent is split by adding 2 N acetic acid.
Fremgangsmåte C: Method C:
Til en oppløsning av 4 g metyl-3-n-butyrylamino-4-fenoksy-5-sulfamyl-benzoat og 1,5 g natriumtetrahydridoborat i 100 ml diglyme dryppe man langsomt en oppløsning av 1 g titantetraklorid i 50 ml diglyme. Oppløsningen skummer opp og det faller ut et blå-grønt bunnfall. Blandingen oppvarmes ca. 3 timer under god omrøring ved 60 - 80°C og blandes deretter forsiktig med 2 N eddiksyre. Isoleringen av metyl-3-n-butylamino-4-fenoksy-5-sulfamyl-benzoat fra To a solution of 4 g of methyl-3-n-butyrylamino-4-phenoxy-5-sulfamyl-benzoate and 1.5 g of sodium tetrahydridoborate in 100 ml of diglyme, a solution of 1 g of titanium tetrachloride in 50 ml of diglyme is slowly dripped. The solution foams up and a blue-green precipitate falls out. The mixture is heated approx. 3 hours with good stirring at 60 - 80°C and then mix carefully with 2 N acetic acid. The isolation of methyl-3-n-butylamino-4-phenoxy-5-sulfamyl-benzoate from
filtratet forløper som ved fremgangsmåte A. the filtrate proceeds as in method A.
Eksempel 3- Example 3-
3- n- butylamino- 4- fenoksy- 5- sulfamyl- benzosyre. 3- n- butylamino- 4- phenoxy- 5- sulfamyl- benzoic acid.
2,5 g metyl-3-n-butylamino-4-fenoksy-5-sulfamyl-benzoat oppløses i 50 ml 1 N NaOH og oppvarmes 30 minutter på dampbad. Deretter filtreres oppløsningen og surgjøres forsiktig. 3-n-butylamino-4- fenoksy-5-sulfamyl-benzosyre av smeltepunkt 229 - 231°C fnokker ut. Etter omkrystallisering fra etanol/vann: Smeltepunkt 235°C. Eksempel 4. 2.5 g of methyl-3-n-butylamino-4-phenoxy-5-sulfamyl-benzoate are dissolved in 50 ml of 1 N NaOH and heated for 30 minutes in a steam bath. The solution is then filtered and carefully acidified. 3-n-butylamino-4-phenoxy-5-sulfamyl-benzoic acid of melting point 229 - 231°C flake out. After recrystallization from ethanol/water: Melting point 235°C. Example 4.
3- n- butyrylamino- 4- fenoksy- 5- sulfamy1- benzosyre. 3- n- butyrylamino- 4- phenoxy- 5- sulfamy1- benzoic acid.
Til den kokende oppløsning av 93 g 3-amino-4-fenoksy-5-sulfamyl-benzosyre og 48 g pyridin i 500 ml dioksan drypper man langsomt under kraftig omrøring en oppløsning av 70 g smørsyreklorid i 300 ml aceton. Etter 7 timer lar man reaksjonsblandingen avkjøle, filtrerer, inndamper til ca. 1/3 av oppløsningsmiddelvolumet og drypper den deretter under god omrøring i en blanding av isvann og 2N saltsyre. Den utfelte 3-butyrylamino-4-fenoksy-5-sulfamyl-benzosyre kan omkrystalliseres av vann/metanol eller iseddik. Smelte- To the boiling solution of 93 g of 3-amino-4-phenoxy-5-sulfamyl-benzoic acid and 48 g of pyridine in 500 ml of dioxane, a solution of 70 g of butyric acid chloride in 300 ml of acetone is added slowly with vigorous stirring. After 7 hours, the reaction mixture is allowed to cool, filtered, evaporated to approx. 1/3 of the solvent volume and then drop it with good stirring into a mixture of ice water and 2N hydrochloric acid. The precipitated 3-butyrylamino-4-phenoxy-5-sulfamyl-benzoic acid can be recrystallized from water/methanol or glacial acetic acid. Melt-
punkt 270 - 271°C. point 270 - 271°C.
Eksempel 5. Example 5.
3- n- butylamino- 4- fenoksy- 5- sulfamyl- benzosyre. 3- n- butylamino- 4- phenoxy- 5- sulfamyl- benzoic acid.
Til en blanding av 6,3 g natrium-3-n-butyrylamino-4-fenoksy-5-sulfamyl-benzoat og 1,2 g natriumtetrahydridoborat i diglyme drypper man en oppløsning av 1,5 g aluminiumtriklorid i diglyme. Deretter oppvarmer man reaksjonsblandingen under kraftig omrøring i 3 timer ved 110 - 120°C og tilsetter endelig noe vann. Reaksjonsblandingen inndampes på rotasjonsfordamper, den gjenblivende olje opp-tass med litt 2 N ammoniakkoppløsning og inndampes til tørrhet. A solution of 1.5 g of aluminum trichloride in diglyme is added dropwise to a mixture of 6.3 g of sodium 3-n-butyrylamino-4-phenoxy-5-sulfamyl-benzoate and 1.2 g of sodium tetrahydridoborate in diglyme. The reaction mixture is then heated with vigorous stirring for 3 hours at 110 - 120°C and finally some water is added. The reaction mixture is evaporated on a rotary evaporator, the remaining oil is taken up with a little 2 N ammonia solution and evaporated to dryness.
Ved tilsetning av litt vann faller det ut ammoniumsaltet av 3-n-butylamino-4-fenoksy-5-sulfamyl-benzosyre. Det oppløses i vann/metanol og tilsettes få dråper 2 N saltsyre. 3-n-butylamino-4-fenoksy-5-sulfamyl-benzosyre krystalliserer ut. When a little water is added, the ammonium salt of 3-n-butylamino-4-phenoxy-5-sulfamyl-benzoic acid precipitates. It is dissolved in water/methanol and a few drops of 2 N hydrochloric acid are added. 3-n-butylamino-4-phenoxy-5-sulfamyl-benzoic acid crystallizes out.
Ge nerell forskrift for acylering av karboksylsyreklorider. General regulations for the acylation of carboxylic acid chlorides.
Til den kokende oppløsning av 0,05 mol aminoforbindelse III og 5 ml pyridin i 100 ml vannfri dioksan drypper man langsomt og under god omrøring en oppløsning av 0,1 mol karboksylsyre-klorid i 100 ml vannfri aceton. Etter ca. 2 til 5 timer, alt etter anvendt syreklorid, er reaksjonen avsluttet. Man inndamper blandingen på reaksjons fordamper, opptar det gjenblivende oljeaktige produkt med litt metanol eller aceton og drypper denne oppløsning under kraftig omrøring i "isvann". Produktet II fnokker ut og suges fra. To the boiling solution of 0.05 mol of amino compound III and 5 ml of pyridine in 100 ml of anhydrous dioxane, a solution of 0.1 mol of carboxylic acid chloride in 100 ml of anhydrous acetone is added slowly and with good stirring. After approx. 2 to 5 hours, depending on the acid chloride used, the reaction is finished. The mixture is evaporated on a reaction evaporator, the remaining oily product is taken up with a little methanol or acetone and this solution is dripped into "ice water" with vigorous stirring. The product II fluffs out and is sucked off.
Generell forskrift til fremstilling av 3- aIkylaminobenzosyrederi-vater med formel I. General regulations for the production of 3-alkylaminobenzoic acid derivatives with formula I.
Til en oppløsning eller suspensjon av 0,03 mol av en forbindelse med formel II i 100 - 150 ml vannfri dietylenglykoldimetyleter (diglyme) har man 8,5 ml BF^-eterat. Deretter lar man langsomt ved værelsestemperatur under god omrøring tildryppe en oppløsning av 2 g NaBHjj i 100 ml diglyme. Etter tildrypningen etteromrører man alt etter anvendt forbindelse II i 30 - 60 minutter ved en temperatur på 20 - 70°C. Reaksjonsavslutningen bestemmes ved hjelp av tynnsjikt-kromatografi. Forbindelsene med formel I sees på kromatogrammet ved 366 nm som lyseblå fluoriserende flekker, mens forbindelsene med formel II ikke fluoriserer. For a solution or suspension of 0.03 mol of a compound of formula II in 100 - 150 ml of anhydrous diethylene glycol dimethyl ether (diglyme), 8.5 ml of BF 2 -etherate is used. A solution of 2 g of NaBHjj in 100 ml of diglyme is then slowly added dropwise at room temperature with good stirring. After the addition, stirring is continued depending on the compound II used for 30 - 60 minutes at a temperature of 20 - 70°C. The completion of the reaction is determined by means of thin-layer chromatography. The compounds of formula I are seen on the chromatogram at 366 nm as pale blue fluorescent spots, while the compounds of formula II do not fluoresce.
Etter tilsetning av litt vann (skumming) spaltes det overskytende reduksjonsmiddel. Deretter filtreres, og produktet utfelles kaldt ved tilsetning av ytterligere 200 ml vann. Produktet fremkommer omtrent rent og frasuges. After the addition of a little water (foaming), the excess reducing agent is decomposed. It is then filtered, and the product is precipitated cold by adding a further 200 ml of water. The product emerges almost clean and is sucked off.
De således dannede estere (Fr - i i H) kan forsåpes med IN NaOH til fri syre. The thus formed esters (Fr - i i H) can be saponified with IN NaOH to free acid.
Man suspenderer den tilsvarende ester i IN NaOH og oppvarmer blandingen på dampbad. Så snart det er oppstått en klar oppløsning lar man det langsomt avkjøle og feller syren med 2N HC1. The corresponding ester is suspended in 1N NaOH and the mixture is heated on a steam bath. As soon as a clear solution has formed, it is allowed to cool slowly and the acid is precipitated with 2N HC1.
Ovennevnte generelle forskrift- er en variant av de i eksemplene 1-5 anvendte arbeidsmåter. De i tabellen angitte eksempler 6-41 ble fremstilt på denne måte. The above general regulations are a variant of the working methods used in examples 1-5. The examples 6-41 indicated in the table were prepared in this way.
Alle forbindelser ifølge oppfinnelsen kan fremstilles etter samtlige angitte varianter. All compounds according to the invention can be produced according to all the specified variants.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO752250A NO142119C (en) | 1973-09-07 | 1975-06-24 | 3-acylamino-5-sulfamyl-benzoic DERIVATIVES |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19732345229 DE2345229C3 (en) | 1973-09-07 | S-Butyrylamino ^ -phenoxy-S-suliamylbenzoic acid derivatives and process for the preparation of substituted 3-butylaminobenzoic acid derivatives |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO743211L NO743211L (en) | 1975-04-01 |
| NO140101B true NO140101B (en) | 1979-03-26 |
| NO140101C NO140101C (en) | 1979-09-05 |
Family
ID=5891979
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO743211A NO140101C (en) | 1973-09-07 | 1974-09-06 | PROCEDURES FOR THE PREPARATION OF SUBSTITUTED AMINOBENZO ACID DERIVATIVES |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US3991097A (en) |
| JP (1) | JPS5756472B2 (en) |
| AT (1) | AT338760B (en) |
| BE (1) | BE819694A (en) |
| CA (1) | CA1027134A (en) |
| CH (1) | CH605715A5 (en) |
| DK (1) | DK472374A (en) |
| FI (1) | FI259974A (en) |
| FR (1) | FR2243186B1 (en) |
| GB (1) | GB1484606A (en) |
| HU (1) | HU170704B (en) |
| IE (1) | IE39836B1 (en) |
| LU (1) | LU70853A1 (en) |
| NL (1) | NL7411618A (en) |
| NO (1) | NO140101C (en) |
| SE (1) | SE411752B (en) |
| ZA (1) | ZA745676B (en) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4093735A (en) * | 1974-04-25 | 1978-06-06 | Hoechst Aktiengesellschaft | 5-Sulfamoylbenzoic acid derivatives carrying a heterocyclic substituent |
| DE2504383A1 (en) * | 1975-02-03 | 1976-08-05 | Bayer Ag | BENZOIC ACID DERIVATIVES, THE PROCESS FOR THEIR PRODUCTION AND THEIR USE AS HERBICIDES |
| US4118587A (en) * | 1976-03-22 | 1978-10-03 | Hoffmann-La Roche Inc. | Novel 4-phenoxy-5-sulfamylbenzoic acid derivatives |
| US4208535A (en) * | 1976-03-22 | 1980-06-17 | Hoffmann-La Roche Inc. | Novel 4-phenoxy-5-sulfamylbenzoic acid |
| EP0008367B1 (en) * | 1978-07-20 | 1983-08-10 | BASF Aktiengesellschaft | N-arylsulfonyl pyrroles, their preparation and medicaments containing them |
| JPS6057976U (en) * | 1983-08-25 | 1985-04-23 | 一色 倫 | Fish hook with return |
| JPS6064060U (en) * | 1983-10-07 | 1985-05-07 | 田中 理 | Fishhook with a twist |
| IS3079A7 (en) * | 1986-02-19 | 1986-10-30 | ævarr Jonsson Sigurbjörn | Automatic fishing line shredder. Line angler, angular seam, trajectory and cane for sharp and unlined line. |
| JPH0385868U (en) * | 1989-12-20 | 1991-08-30 | ||
| US8722668B2 (en) * | 1998-12-23 | 2014-05-13 | Daryl W. Hochman | Methods and compositions for the treatment of neuropathic pain and neuropsychiatric disorders |
| US8008283B2 (en) * | 1998-12-23 | 2011-08-30 | Neurotherapeutics Pharma, Inc. | Methods and compositions for the treatment of neuropsychiatric disorders |
| US7214711B2 (en) * | 1998-12-23 | 2007-05-08 | Neurotherapeutics Pharma Llc | Method of treating migraine headache without aura |
| WO2007047447A2 (en) * | 2005-10-17 | 2007-04-26 | Neurotherapeutics Pharma, Inc. | Diuretic-like compound analogs useful for regulation of central nervous system disorders |
| CN116041228B (en) * | 2022-05-16 | 2024-03-12 | 沈阳希贝康医药科技有限公司 | Synthesis method of bumetanide |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB1249490A (en) * | 1968-12-24 | 1971-10-13 | Leo Pharm Prod Ltd | New sulphamyl-benzoic acid derivatives |
-
1974
- 1974-09-02 NL NL7411618A patent/NL7411618A/en not_active Application Discontinuation
- 1974-09-04 CH CH1199574A patent/CH605715A5/xx not_active IP Right Cessation
- 1974-09-04 HU HUHO1715A patent/HU170704B/hu unknown
- 1974-09-05 FI FI2599/74A patent/FI259974A/fi unknown
- 1974-09-05 US US05/503,280 patent/US3991097A/en not_active Expired - Lifetime
- 1974-09-05 LU LU70853A patent/LU70853A1/xx unknown
- 1974-09-06 IE IE1857/74A patent/IE39836B1/en unknown
- 1974-09-06 CA CA208,650A patent/CA1027134A/en not_active Expired
- 1974-09-06 DK DK472374A patent/DK472374A/da not_active Application Discontinuation
- 1974-09-06 SE SE7411290A patent/SE411752B/en unknown
- 1974-09-06 AT AT720474A patent/AT338760B/en not_active IP Right Cessation
- 1974-09-06 GB GB39111/74A patent/GB1484606A/en not_active Expired
- 1974-09-06 ZA ZA00745676A patent/ZA745676B/en unknown
- 1974-09-06 NO NO743211A patent/NO140101C/en unknown
- 1974-09-07 JP JP49102530A patent/JPS5756472B2/ja not_active Expired
- 1974-09-09 FR FR7430461A patent/FR2243186B1/fr not_active Expired
- 1974-09-09 BE BE148339A patent/BE819694A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| FI259974A (en) | 1975-03-08 |
| IE39836L (en) | 1975-03-07 |
| BE819694A (en) | 1975-03-10 |
| US3991097A (en) | 1976-11-09 |
| DE2345229B2 (en) | 1976-11-11 |
| SE7411290L (en) | 1975-03-10 |
| ZA745676B (en) | 1975-09-24 |
| JPS5052042A (en) | 1975-05-09 |
| HU170704B (en) | 1977-08-28 |
| GB1484606A (en) | 1977-09-01 |
| ATA720474A (en) | 1977-01-15 |
| AU7300674A (en) | 1976-03-11 |
| AT338760B (en) | 1977-09-12 |
| LU70853A1 (en) | 1976-08-19 |
| NL7411618A (en) | 1975-03-11 |
| FR2243186A1 (en) | 1975-04-04 |
| SE411752B (en) | 1980-02-04 |
| DK472374A (en) | 1975-05-05 |
| CA1027134A (en) | 1978-02-28 |
| NO743211L (en) | 1975-04-01 |
| CH605715A5 (en) | 1978-10-13 |
| JPS5756472B2 (en) | 1982-11-30 |
| DE2345229A1 (en) | 1975-03-13 |
| FR2243186B1 (en) | 1977-10-28 |
| IE39836B1 (en) | 1979-01-17 |
| NO140101C (en) | 1979-09-05 |
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